Peroxisome proliferator-activated receptor γ (“PPARγ”) is one member of the nuclear receptor superfamily of ligand-activated transcription factors and has been shown to be expressed primarily in an adipose tissue-specific manner. Its expression is induced early during the course of differentiation of several preadipocyte cell lines. Additional research has now demonstrated that PPARγ plays a pivotal role in the adipogenic signaling cascade. PPARγ also regulates the ob/leptin gene which is involved in regulating energy homeostasis and adipocyte differentiation, which has been shown to be a critical step to be targeted for treating disorders such as obesity, diabetes and dyslipidemia.
In view of the clinical importance of PPARγ, compounds that modulate PPARγ function can be used for the development of new therapeutic agents. Potent modulators of PPARγ have been described, for example, in International Patent Publication No. WO 01/00579, and U.S. Pat. Nos. 6,200,995 B1, 6,583,157 B2, 6,653,332 B2, and 7,041,691 B1. One of these promising modulators, identified herein as compound 101 (or compound of formula (I)), is in clinical development for therapeutic treatment of Type 2 Diabetes. A suitable pharmaceutical composition or dosage form for this molecule is essential for its use in the prevention or treatment of disease. Pharmaceutical compositions that improve stability, increase bioavailability and improve ease of administration would be particularly useful. Dosage forms capable of facilitating administration of combination therapies are also desirable.
The free base and certain pharmaceutically acceptable salts of compound 101 are described in International Patent Publication No. WO01/00579, and U.S. Pat. Nos. 6,583,157 B2 and 7,041,691 B1. U.S. Pat. No. 7,223,761 B2 discloses that the benzenesulfonic acid (besylate) salt of compound 101, and polymorphs thereof, displays superior stability and hygroscopic properties when compared to other salts of compound 101. Despite the superior stability and hygroscopic properties of the besylate salt of compound 101, the besylate salt is sparingly soluble in aqueous solvents and in most organic solvents, which severely limits its effective concentration in a pharmaceutical preparation and can lead to decreased bioavailability upon administration.
U.S. Provisional Patent Application No. 61/102,658, discloses oral pharmaceutical preparations comprising liquid (oil-based) formulations of the besylate salt of compound 101 in a capsule. Despite the desirable solubility and bioavailability observed for the besylate salt of compound 101 in the oil-based formulation, the capsules are prone to leakage or precipitation of their contents over time. Leakage of the capsules' contents over time may result in loss of the active ingredient in the capsule, and may further result in a contamination of the contents of the capsule. Precipitation of the capsules' contents over time may result in loss of bioavailability.
A need therefore exists for a pharmaceutical composition of besylate and other salt and polymorphic forms of this class of PPARγ modulators which displays suitable bioavailability and shelf-life stability, and which is not susceptible to liquid capsule leakage over time. These and other unmet needs are addressed by this disclosure.